3D-QSAR studies of heterocyclic quinones with inhibitory activity on vascular smooth muscle cell proliferation using pharmacophore-based alignment.
The abnormal proliferation and migration of vascular smooth muscle cells (SMCs) play an important role in the pathology of coronary artery atherosclerosis and restenosis following angioplasty. It was reported that some heterocyclic quinone derivatives such as 6-arylamino-quinoxaline-5,8-diones and 6-arylamino-1H-benzo[d]imidazole-4,7-diones have inhibitory activity on rat aortic smooth muscle cell (RAoSMC) proliferation. To understand the structural basis for antiproliferative activity to design more potent agents, we generated pharmacophore models of representative molecules with high activity using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) and aligned a series of compounds to the selected pharmacophore model, then performed three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Good cross-validated correlations were obtained with CoMFA (resulting in q(2) of 0.734 and r(2) of 0.947) and CoMSIA (resulting in q(2) of 0.736 and r(2) of 0.913). The IC(50) values of the heterocyclic quinone derivatives on RAoSMC exhibited a strong correlation with steric and hydrophobic fields of the 3D structure of the molecules, resulting in the reliable prediction of inhibitory activity of the series of compounds.
Ryu
Chung-Kyu
CK
College of Pharmacy and Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea. ckryu@mm.ewha.ac.kr
Lee
Yoonji
Y
Park
Seul-gi
SG
You
Hea-Jung
HJ
Lee
Ra-Young
RY
Lee
Seung-Yon
SY
Choi
Sun
S
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats
D011809:Quinones